Compounds for treating beta-amyloidoses

Abstract

The present invention relates to the use of mimotopes in the treatment of diseases associated with β-amyloid formation and/or aggregation (β-Amyloidoses) including Alzheimer's disease, whereby said mimotopes are able to induce the in vivo formation of antibodies directed to Aβ1-40/42, AβpE3-40/42, Aβ3-40/42 and Aβ11-40/42.

1 . A process for preventing, treating, or both preventing and treating β-amyloidoses, the process comprising administering to an individual a medicament comprising a compound comprising an amino acid sequence selected from the group consisting of SEFKHG(C) (SEQ ID NO: 124), TLHEFRH(C) (SEQ ID NO: 151), ILFRHG(C) (SEQ ID NO: 133), TSVFRH(C) (SEQ ID NO: 126), SQFRHY(C) (SEQ ID NO: 128), LMFRHN(C) (SEQ ID NO: 129), SPNQFRH(C) (SEQ ID NO: 143), ELFKHHL(C) (SEQ ID NO: 150), THTDFRH(C) (SEQ ID NO: 160), DEHPFRH(C) (SEQ ID NO: 164), QSEFKHW(C) (SEQ ID NO: 172), ADHDFRH(C) (SEQ ID NO: 174), YEFRHAQ(C) (SEQ ID NO: 182) and TEFRHKA(C) (SEQ ID NO: 187). 
     
     
         2 . A process for preventing, treating, or both preventing and treating β-amyloidoses, the process comprising administering to an individual a medicament comprising a compound comprising an amino acid sequence
   X 1 RX 2 DX 3 (X 4 ) n (X 5 ) m (X 6 ) o  (SEQ ID NO: 100)  (Formula I),
 
 wherein 
 X 1  is isoleucine (I) or valine (V), 
 X 2  is tryptophan (W) or tyrosine (Y), 
 X 3  is threonine (T), valine (V), alanine (A), methionine (M), glutamine (Q) or glycine (G), 
 X 4  is proline (P), alanine (A), tyrosine (Y), serine (5), cysteine (C) or glycine (G), 
 X 5  is proline (P), leucine (L), glycine (G) or cysteine (C), 
 X 6  is cysteine (C), 
 n, m and o are, independently, 0 or 1, 
 wherein the compound has a binding capacity to an antibody which is specific for an epitope of an amyloid-beta-peptide (Aβ) comprising an amino acid sequence EFRHDSGY (SEQ ID NO: 102) or pEFRHDSGY (SEQ ID NO: 103). 
 
     
     
         3 . The process of  claim 2 , wherein the compound comprises an amino acid sequence selected from the group consisting of IRWDTP(C) (SEQ ID NO: 106), VRWDVYP(C) (SEQ ID NO: 107), IRYDAPL(C) (SEQ ID NO: 108), IRYDMAG(C) (SEQ ID NO: 109), IRWDTSL(C) (SEQ ID NO: 110), IRWDQP(C) (SEQ ID NO: 111), IRWDG(C) (SEQ ID NO: 112) and IRWDGG(C) (SEQ ID NO: 113). 
     
     
         4 . A process for preventing, treating, or both preventing and treating β-amyloidoses, the process comprising administering to an individual a medicament comprising a compound comprising an amino acid sequence
   EX 1 WHX 2 X 3 (X 4 ) n (X 5 ) m  (SEQ ID NO: 101)  (Formula II),
 
 wherein 
 X 1  is valine (V), arginine (R) or leucine (L), 
 X 2  is arginine (R) or glutamic acid (E), 
 X 3  is alanine (A), histidine (H), lysine (K), leucine (L), tyrosine (Y) or glycine (G), 
 X 4  is proline (P), histidine (H), phenylalanine (F) or glutamine (Q) or Cysteine 
 X 5  is cysteine (C), 
 n and m are, independently, 0 or 1, 
 wherein the compound has a binding capacity to an antibody which is specific for an epitope of an amyloid-beta-peptide (Aβ) comprising an amino acid sequence EVHHQKL (SEQ ID NO: 104). 
 
     
     
         5 . The process of  claim 4 , wherein the compound comprises an amino acid sequence selected from the group consisting of EVWHRHQ(C) (SEQ ID NO: 114), ERHEKH(C) (SEQ ID NO: 115), EVWHRLQ(C) (SEQ ID NO: 116), ELWHRYP(C) (SEQ ID NO: 117), ELWHRAF(C) (SEQ ID NO: 118), ELWHRA(C) (SEQ ID NO: 119), EVWHRG(C) (SEQ ID NO: 120), EVWHRH(C) (SEQ ID NO: 121) and ERHEK(C) (SEQ ID NO: 122). 
     
     
         6 . A process for preventing, treating, or both preventing and treating β-amyloidoses, the process comprising administering to an individual a medicament comprising a compound comprising an amino acid sequence selected from the group consisting of QDFRHY(C) (SEQ ID NO: 123), SEFKHG(C) (SEQ ID NO: 124), TSFRHG(C) (SEQ ID NO: 125), TSVFRH(C) (SEQ ID NO: 126), TPFRHT(C) (SEQ ID NO: 127), SQFRHY(C) (SEQ ID NO: 128), LMFRHN(C) (SEQ ID NO: 129), SAFRHH(C) (SEQ ID NO: 130), LPFRHG(C) (SEQ ID NO: 131), SHFRHG(C) (SEQ ID NO: 132), ILFRHG(C) (SEQ ID NO: 133), QFKHDL(C) (SEQ ID NO: 134), NWFPHP(C) (SEQ ID NO: 135), EEFKYS(C) (SEQ ID NO: 136), NELRHST(C) (SEQ ID NO: 137), GEMRHQP(C) (SEQ ID NO: 138), DTYFPRS(C) (SEQ ID NO: 139), VELRHSR(C) (SEQ ID NO: 140), YSMRHDA(C) (SEQ ID NO: 141), AANYFPR(C) (SEQ ID NO: 142), SPNQFRH(C) (SEQ ID NO: 143), SSSFFPR(C) (SEQ ID NO: 144), EDWFFWH(C) (SEQ ID NO: 145), SAGSFRH(C) (SEQ ID NO: 146), QVMRHHA(C) (SEQ ID NO: 147), SEFSHSS(C) (SEQ ID NO: 148), QPNLFYH(C) (SEQ ID NO: 149), ELFKHHL(C) (SEQ ID NO: 150), TLHEFRH(C) (SEQ ID NO: 151), ATFRHSP(C) (SEQ ID NO: 152), APMYFPH(C) (SEQ ID NO: 153), TYFSHSL(C) (SEQ ID NO: 154), HEPLFSH(C) (SEQ ID NO: 155), SLMRHSS(C) (SEQ ID NO: 156), EFLRHTL(C) (SEQ ID NO: 157), ATPLFRH(C) (SEQ ID NO: 158), QELKRYY(C) (SEQ ID NO: 159), THTDFRH(C) (SEQ ID NO: 160), LHIPFRH(C) (SEQ ID NO: 161), NELFKHF(C) (SEQ ID NO: 162), SQYFPRP(C) (SEQ ID NO: 163), DEHPFRH(C) (SEQ ID NO: 164), MLPFRHG(C) (SEQ ID NO: 165), SAMRHSL(C) (SEQ ID NO: 166), TPLMFWH(C) (SEQ ID NO: 167), LQFKHST(C) (SEQ ID NO: 168), ATFRHST(C) (SEQ ID NO: 169), TGLMFKH(C) (SEQ ID NO: 170), AEFSHWH(C) (SEQ ID NO: 171), QSEFKHW(C) (SEQ ID NO: 172), AEFMHSV(C) (SEQ ID NO: 173), ADHDFRH(C) (SEQ ID NO: 174), DGLLFKH(C) (SEQ ID NO: 175), IGFRHDS(C) (SEQ ID NO: 176), SNSEFRR(C) (SEQ ID NO: 177), SELRHST(C) (SEQ ID NO: 178), THMEFRR(C) (SEQ ID NO: 179), EELRHSV(C) (SEQ ID NO: 180), QLFKHSP(C) (SEQ ID NO: 181), YEFRHAQ(C) (SEQ ID NO: 182), SNFRHSV(C) (SEQ ID NO: 183), APIQFRH(C) (SEQ ID NO: 184), AYFPHTS(C) (SEQ ID NO: 185), NSSELRH(C) (SEQ ID NO: 186), TEFRHKA(C) (SEQ ID NO: 187), TSTEMWH(C) (SEQ ID NO: 188), SQSYFKH(C) (SEQ ID NO: 189), (C)SEFKH (SEQ ID NO: 190), SEFKH(C) (SEQ ID NO: 191), (C)HEFRH (SEQ ID NO: 192) and HEFRH(C) (SEQ ID NO: 193). 
     
     
         7 . The process of  claim 6 , wherein the compound comprises an amino acid sequence selected from the group consisting of QDFRHY(C) (SEQ ID NO: 123), SEFKHG(C) (SEQ ID NO: 124), TSFRHG(C) (SEQ ID NO: 125), TSVFRH(C) (SEQ ID NO: 126), TPFRHT(C) (SEQ ID NO: 127), SQFRHY(C) (SEQ ID NO: 128), LMFRHN(C) (SEQ ID NO: 129), SAFRHH(C) (SEQ ID NO: 130), LPFRHG(C) (SEQ ID NO: 131), SHFRHG(C) (SEQ ID NO: 132), ILFRHG(C) (SEQ ID NO: 133), QFKHDL(C) (SEQ ID NO: 134), NWFPHP(C) (SEQ ID NO: 135), EEFKYS(C) (SEQ ID NO: 136), SPNQFRH(C) (SEQ ID NO: 143), ELFKHHL(C) (SEQ ID NO: 150), TLHEFRH(C) (SEQ ID NO: 151), THTDFRH(C) (SEQ ID NO: 160), DEHPFRH(C) (SEQ ID NO: 164), QSEFKHW(C) (SEQ ID NO: 172), ADHDFRH(C) (SEQ ID NO: 174), DGLLFKH(C) (SEQ ID NO: 175), EELRHSV(C) (SEQ ID NO: 180), YEFRHAQ(C) (SEQ ID NO: 182), TEFRHKA(C) (SEQ ID NO: 187), (C)SEFKH (SEQ ID NO: 190), SEFKH(C) (SEQ ID NO: 191), (C)HEFRH (SEQ ID NO: 192) and HEFRH(C) (SEQ ID NO: 193). 
     
     
         8 . The process of  claim 6 , wherein the compound is a polypeptide comprising 7 to 20 amino acid residues. 
     
     
         9 . The process of  claim 6 , wherein the compound is coupled to a pharmaceutically acceptable carrier. 
     
     
         10 . The process of  claim 6 , wherein the compound is formulated for intravenous, subcutaneous, intradermal or intramuscular administration. 
     
     
         11 . The process of  claim 6 , wherein the compound is formulated with an adjuvant. 
     
     
         12 . The process of  claim 6 , wherein the medicament comprises 0.1 ng to 10 mg of the compound, preferably 10 ng to 1 mg, in particular 100 ng to 10 μg. 
     
     
         13 . An isolated peptide comprising an amino acid sequence selected from the group consisting of IRWDTP(C) (SEQ ID NO: 106), VRWDVYP(C) (SEQ ID NO: 107), IRYDAPL(C) (SEQ ID NO: 108), IRYDMAG(C) (SEQ ID NO: 109), IRWDTSL(C) (SEQ ID NO: 110), IRWDQP(C) (SEQ ID NO: 111), IRWDG(C) (SEQ ID NO: 112), IRWDGG(C) (SEQ ID NO: 113), EVWHRHQ(C) (SEQ ID NO: 114), ERHEKH(C) (SEQ ID NO: 115), EVWHRLQ(C) (SEQ ID NO: 116), ELWHRYP(C) (SEQ ID NO: 117), ELWHRAF(C) (SEQ ID NO: 118), ELWHRA(C) (SEQ ID NO: 119), EVWHRG(C) (SEQ ID NO: 120), EVWHRH(C) (SEQ ID NO: 121), ERWHEK(C) (SEQ ID NO: 122), QDFRHY(C) (SEQ ID NO: 123), SEFKHG(C) (SEQ ID NO: 124), TSFRHG(C) (SEQ ID NO: 125), TSVFRH(C) (SEQ ID NO: 126), TPFRHT(C) (SEQ ID NO: 127), SQFRHY(C) (SEQ ID NO: 128), LMFRHN(C) (SEQ ID NO: 129), SAFRHH(C) (SEQ ID NO: 130), LPFRHG(C) (SEQ ID NO: 131), SHFRHG(C) (SEQ ID NO: 132), ILFRHG(C) (SEQ ID NO: 133), QFKHDL(C) (SEQ ID NO: 134), NWFPHP(C) (SEQ ID NO: 135), EEFKYS(C) (SEQ ID NO: 136), NELRHST(C) (SEQ ID NO: 137), GEMRHQP(C) (SEQ ID NO: 138), DTYFPRS(C) (SEQ ID NO: 139), VELRHSR(C) (SEQ ID NO: 140), YSMRHDA(C) (SEQ ID NO: 141), AANYFPR(C) (SEQ ID NO: 142), SPNQFRH(C) (SEQ ID NO: 143), SSSFFPR(C) (SEQ ID NO: 144), EDWFFWH(C) (SEQ ID NO: 145), SAGSFRH(C) (SEQ ID NO: 146), QVMRHHA(C) (SEQ ID NO: 147), SEFSHSS(C) (SEQ ID NO: 148), QPNLFYH(C) (SEQ ID NO: 149), ELFKHHL(C) (SEQ ID NO: 150), TLHEFRH(C) (SEQ ID NO: 151), ATFRHSP(C) (SEQ ID NO: 152), APMYFPH(C) (SEQ ID NO: 153), TYFSHSL(C) (SEQ ID NO: 154), HEPLFSH(C) (SEQ ID NO: 155), SLMRHSS(C) (SEQ ID NO: 156), EFLRHTL(C) (SEQ ID NO: 157), ATPLFRH(C) (SEQ ID NO: 158), QELKRYY(C) (SEQ ID NO: 159), THTDFRH(C) (SEQ ID NO: 160), LHIPFRH(C) (SEQ ID NO: 161), NELFKHF(C) (SEQ ID NO: 162), SQYFPRP(C) (SEQ ID NO: 163), DEHPFRH(C) (SEQ ID NO: 164), MLPFRHG(C) (SEQ ID NO: 165), SAMRHSL(C) (SEQ ID NO: 166), TPLMFWH(C) (SEQ ID NO: 167), LQFKHST(C) (SEQ ID NO: 168), ATFRHST(C) (SEQ ID NO: 169), TGLMFKH(C) (SEQ ID NO: 170), AEFSHWH(C) (SEQ ID NO: 171), QSEFKHW(C) (SEQ ID NO: 172), AEFMHSV(C) (SEQ ID NO: 173), ADHDFRH(C) (SEQ ID NO: 174), DGLLFKH(C) (SEQ ID NO: 175), IGFRHDS(C) (SEQ ID NO: 176), SNSEFRR(C) (SEQ ID NO: 177), SELRHST(C) (SEQ ID NO: 178), THMEFRR(C) (SEQ ID NO: 179), EELRHSV(C) (SEQ ID NO: 180), QLFKHSP(C) (SEQ ID NO: 181), YEFRHAQ(C) (SEQ ID NO: 182), SNFRHSV(C) (SEQ ID NO: 183), APIQFRH(C) (SEQ ID NO: 184), AYFPHTS(C) (SEQ ID NO: 185), NSSELRH(C) (SEQ ID NO: 186), TEFRHKA(C) (SEQ ID NO: 187), TSTEMWH(C) (SEQ ID NO: 188), SQSYFKH(C) (SEQ ID NO: 189), (C)SEFKH (SEQ ID NO: 190), SEFKH(C) (SEQ ID NO: 191), (C)HEFRH (SEQ ID NO: 192) and HEFRH(C) (SEQ ID NO: 193). 
     
     
         14 . A process for treating, ameliorating symptoms of, or both treating and ameliorating symptoms of a synucleopathy, the process comprising administering to an individual a medicament comprising the peptide of  claim 13 . 
     
     
         15 . The process of  claim 14 , wherein the synucleopathy is selected from the group consisting of Parkinson's Disease, Dementia with Lewy Bodies, multiple system atrophy and neurodegeneration with brain iron accumulation. 
     
     
         16 . A compound comprising the peptide of  claim 13 , coupled to a pharmaceutically acceptable carrier. 
     
     
         17 . A pharmaceutical formulation comprising the peptide of  claim 13 . 
     
     
         18 . A vaccine comprising the peptide of  claim 13 . 
     
     
         19 . The process of  claim 9 , wherein the pharmaceutically acceptable carrier is KLH (Keyhole Limpet Hemocyanin). 
     
     
         20 . The process of  claim 11 , wherein the adjuvant is aluminium hydroxide.